Great. Welcome. My name is Michael Schmidt. I'm one of the senior biotech analysts at Guggenheim. It is my great pleasure to welcome Deciphera as the next company here with the Fireside Chat. With us, we have Steve Hoerter, CEO. Steve, welcome. Thanks for joining us. Yeah. Thanks, Michael. Pleasure to be here. Right. Kicking it right off with a Q&A. I think most folks are familiar with the company. As we start out talking about QINLOCK, obviously, where you recently announced a major update in January to initiate a new phase III study, INSIGHT, in a second-line GIST setting. Just remind us again of the mechanistic rationale perhaps behind the exploratory analysis that really supported that new phase III study. Sure. Maybe where I'll start, Michael, is just to remind folks that QINLOCK's been approved now in 12 jurisdictions around the world in fourth-line GIST. The basis for that initial approval, which occurred in the U.S. in 2020, was a study called INVICTUS, where we demonstrated really compelling benefit, both in terms of PFS as well as overall survival in that fourth-line setting. We ran a second-line setting called the INTRIGUE study that we reported out at the ASCO Plenary Series session now just over 1 year ago, so it was January of last year, showing the study failed to meet the primary endpoint of showing superiority versus SUTENT in an all-comer population in second-line GIST, but showed efficacy that was seemed to be equivalent as measured by PFS, and also showed that in terms of tolerability, that the drug was much better tolerated. Similar to what we did in the INVICTUS study, in the INTRIGUE study, we also collected peripheral blood samples, and that was longitudinally, so baseline as well as throughout the course of the study. Last year, after the study read out, we then analyzed those samples, looking for ctDNA, and we did that using the Guardant360 platform. That was the basis for the data presentation that we made, the release we had early in January, then the data presentation that was just about three weeks ago at the ASCO Plenary Series session, yet again showing in a subset of patients with 11, 17, 18 mutations, really striking benefit for patients treated with QINLOCK versus sunitinib. The objective response rate was 44% in the QINLOCK arm versus zero for SUTENT. PFS was over 14 months for QINLOCK versus just over a month for SUTENT. We saw also a meaningful benefit in terms of overall survival, which I think was most interesting given subsequent treatment and despite subsequent treatment. There were twice as many patients on the QINLOCK arm alive at two and half years versus patients on the SUTENT arm. Those data were really exciting. We've talked about the data to the FDA. We also spoke with investigators and thought leaders and heard from investigators and thought leaders, considerable enthusiasm for evaluating our drug QINLOCK versus SUTENT in this selected population. That was really the origin of running this new INSIGHT study, which we disclosed at the beginning of the year and which we expect to kick off later in the year. Your question, I think, Michael, started with what is the biologic rationale for why you would see this sort of differential activity in this group of patients? It really boils down to where these drugs bind and how they bind differently. SUTENT is an ATP competitive binding agent. That's the site of these 13, 14 secondary mutations, whereas we bind differently to the switch region of the kinase, and on the activation loop is where the 17, 18 mutations occur. I think what surprised all of us was just the magnitude of the benefit and how differentiating it was in this group of patients for QINLOCK versus SUTENT. Great. You're obviously using a test, a ctDNA-based diagnostic. Perhaps talk about how the ctDNA test differs from, you know, more traditional tumor biopsies as we think about the KIT mutation detection and, you know, how might that diagnostic play out in the real world, perhaps? Yeah. I think, you know, one of the things to note, for those who aren't familiar, one of the hallmarks of this disease of GIST is the polyclonality of the disease. You can imagine in a patient with multiple disease sites, it becomes really challenging using traditional tissue biopsy to detect the range of mutations that may be driving a particular patient's disease. One of the elegant features, we think, of using ctDNA as a diagnostic. It's a simple blood draw. A tube of blood is drawn and sent off to the lab, a 5- to 10-day turnaround time before you then know what that patient's mutation profile is based on circulating tumor DNA. We think that's quite an attractive approach in this disease in particular, where, as I said, using a tissue-based diagnostic, you couldn't fully understand that patient's disease. Now, when it comes to actual commercial application, in the real-world setting, this certainly would not be the first ctDNA-based diagnostic. These diagnostics are widely used. Lung cancer is probably the best example for EGFR mutant disease, we know that a ctDNA-based platform is used quite commonly in lung cancer. There are multiple providers, whether it's Guardant Health with their Guardant360 platform, Foundation Medicine. There are other providers as well, who specialize in evaluating ctDNA based on blood samples. We don't view this as being a barrier at all to physicians now for the first time being able to better understand the mutation profile for a patient with GIST. Yeah. Then remind us of the frequency of the exon 11 and 17, 18, you know, mutation patients. You know, I know in your INTRIGUE analysis, not all patients had, you know, detectable ctDNA. Mm-hmm ... or mutations. For that matter. I guess how do you think about that playing out in your INSIGHT study and how should we think about the timeline for enrolling this phase III, which is fairly small actually? Yeah. It is. Yeah. Thanks, Michael. Let me try and tick through those questions that you asked, which are all really good ones. We know GIST is a KIT-driven disease, so 70% of this disease is KIT-driven. When it comes to the specific subset of patients that we would be looking for, the KIT primary 11, 17/18 secondary, this is about 15% of patients, as we saw from the INTRIGUE study. One of the beauties about this, the INSIGHT study and the approach that we're taking is we have a set of very robust data from INTRIGUE using the ctDNA platform, the Guardant platform, in a wide range of patients from around the world. We have a high degree of certainty in terms of the findings that we see in this analysis from the INTRIGUE study. I think your other question was then with respect to ctDNA not detected. That fraction in this analysis from INTRIGUE was about 22% of patients, not dissimilar from what you see with any other solid tumor when you look at ctDNA, so this isn't surprising. It's not unique to GIST. In terms of enrollment for INSIGHT, we have, as you know, a lot of experience now running large randomized studies around the world. We have longstanding relationships with these investigators and thought leaders. We certainly don't view ctDNA as being a barrier at all to enrolling a study like the INSIGHT study. We're seeking to enroll the same approximate number of patients in INSIGHT as we saw in INTRIGUE with this specific mutational background. While we need to screen using ctDNA, using a blood draw to identify these patients, we think that physicians, based on the feedback so far, investigators are gonna be quite enthusiastic about this idea, the opportunity to, for the first time, be able to identify patients with a specific mutational subset that have the potential to benefit dramatically from a single monotherapy treatment like QINLOCK. We don't view that as being a barrier to enrollment of the INSIGHT study. Right. We're excited to get it started. We have experience, as I said, a lot of enthusiasm from potential sites, and we're looking forward to getting the study off the ground and generating the data. Yeah. The treatment effect was, you know, quite sizable in your analysis. How does that, or how did you power the INSIGHT study as we think about the data that you have in hand? The hazard ratio that we saw in the INSIGHT study for PFS was around about 0.2, a very dramatic effect for PFS. When we thought about powering for the INSIGHT study and designing the INSIGHT study, we wanted to make sure that we weren't changing any meaningful variables in the study relative to what we had done with the INTRIGUE study. Whether it's the dose and schedule of SUTENT or other variables, we wanted to make sure that we kept those constant, aside from the subset or the group of patients that we were going to be identifying. We think we could see in the INSIGHT study a near doubling even of that hazard ratio and still have a statistically significant result from the INSIGHT study. We think the study's well-powered to detect the effect that we need to detect in order to see a positive outcome and potentially serve as the basis for approval. Right. As we think of the sort of emerging landscape in the second-line GIST setting, there's obviously SUTENT, there's also other KIT inhibitors that are being evaluated in combination. You know, how do you think about the sort of evolution of the treatment landscape in, in second-line GIST, and how do you think about, you know, QINLOCK in that context? Yeah. Now, what we're seeing now I believe, based on these results, is the opportunity for the first time in the second line to identify patients for specific treatments. I think the sort of drug development of the 1990s, which is, you know, kind of throwing multiple things at all patients irrespective of your knowledge of what their mutational status is likely to become a thing of the past as we're now able to use a non-invasive tool like ctDNA to select patients. We think we're really at the forefront of what will be a fundamental change in how GIST gets treated, with the adoption of ctDNA-based diagnostics to then tailor treatment for a patient. Whether that's a drug like QINLOCK for patients with the KIT exon 11, 17/80 set of mutations, or SUTENT for the group of patients with the 13/14 mutation, or selecting for avapritinib, for example, patients with PDGFRα mutations. This I think is going to be how the field evolves, and I think there's a high degree of excitement among physicians that this has finally, this era has now finally arrived in the treatment of GIST, whereas previously, you know, the treatment approach in this disease, as you know, Michael, was simply line by line. It was, you know, first imatinib, then it was SUTENT, then it was Rego, and then you move on to QINLOCK in the fourth-line setting. There is a palpable degree of enthusiasm for changing that paradigm, and I think we're gonna help to drive that. Then maybe switching over to the, you know, the commercial, you know, setting, you know, in the fourth line GIST, which is the approved indication, QINLOCK is now generating around $130 million per year in sales. There has been some variability ex-U.S., but I think the product's been growing consistently in the U.S. You've guided to sort of peak sales of around $200 million in the U.S. Can you talk about your confidence in, you know, reaching that, and what are some of the drivers to get you to that sort of number? Sure. In the U.S., year-over-year, we saw about 20% growth with the brand, and that was driven by volume growth. That was about half of that growth, and the rest came from a reduction in the number of patients getting free drug and some price growth. We're seeing good growth in the brand in the U.S. and that's really driven by an extending duration of treatment. As you'll recall, in INVICTUS, the median PFS was about 6.3 months. We now see in the market over the last year about a seven month duration of treatment in this real-world context, and we expect that to continue to grow. We expect at peak it will be somewhere in the range of eight months to eight and half months. That's how the U.S. business will evolve in the fourth-line indication. The opportunity to get to a peak revenue opportunity in the U.S. of $175 million-$200 million is really driven by that growth in duration and growth in price over time. That will be complemented by expanding access to the drug outside of the U.S. We're approved, as I mentioned, in 12 different jurisdictions. That includes in the EU, also in Switzerland, and in the U.K. The team is very actively working through the pricing and reimbursement negotiation process, not only in Germany, but also in France. In Italy, we've started the process also with NICE in England and Wales, and also in Spain. We would expect over the course of the year that we'll make considerable progress in opening up the number of markets and expanding the number of markets where patients have access. In its totality, when we think of the brand globally, we think we're really just at the beginning, not only in terms of geographic expansion, but also as we see the growth and volume in the U.S. being driven by duration. Adding to that, of course, is this opportunity with the INSIGHT study in the second-line setting, where we expect that to nearly double the revenue opportunity in the U.S. alone, based on the fourth-line business that exists today. How should we think about the peak sales potential in fourth-line GIST in Europe? Difficult for us to project right now, principally because we haven't completed the pricing and reimbursement negotiation process. We're nearing conclusion of that process in Germany, and then as I mentioned, we'll be knocking down other markets on a one-by-one basis. As soon as we get to an understanding of what net average price will be across Europe, I think we'll be in a much better position to try to project what we see as the peak opportunity in Europe specifically. That, of course, doesn't include other territories. We're partnered with Zai Lab in China. Zai was successful in getting QINLOCK listed on the National Reimbursement Drug List, and that was announced very recently. We have distribution partners in Australia, New Zealand, and Canada, also in Israel. We now have expanding approvals, as I mentioned, now with an approval in Israel, an approval in Macau, for example. We'll continue to expand the number of territories where the drug is available over the course of the year. Great. Assuming success of the INSIGHT study in a second-line setting, to what degree do you think that might cannibalize use in fourth line? It's really going to be the math here in terms of the opportunity and the upside with a second-line opportunity is really about more patients and longer duration. We know that not all patients who are treated in the second line make it to the fourth-line setting. We see about 50% attrition from second line to fourth line unfortunately, where patients just do not do well on existing therapies and don't have the opportunity to benefit from subsequent treatment. We're able, therefore, to capture more patients in the second line by getting a label in the second-line setting. We also know from the data that I mentioned with a 14, over a 14-month PFS in that second-line setting that we're gonna see longer duration of treatment for those patients, whether they are the patients who don't make it onto the fourth line or even patients who get treated now in the second line and therefore don't get treated in the fourth-line setting. We still will see longer duration. Taken together, we think it's a doubling of the opportunity in the U.S. Great. Great. Great. Maybe then switching gears over to vimseltinib, which is your, you know, your product candidate that's in phase III right now. You have reported data recently at ESMO that looked quite compelling. We, I believe we will get some additional updates from the phase I, II, later this year. Perhaps talk about how we should think about the overall clinical profile of vimseltinib based on the available data so far, and perhaps also relative to Turalio, which is approved in indication. Yeah, I'll start, Michael, with the data from ESMO last year from the phase I, II study. The most mature data set that we have is the group of patients from the dose escalation part of the phase I, where we now see a 69% response rate. These are the data we presented at ESMO. We see an average duration of treatment in those patients of closing in on 18 months, so it's about seventeen and a half months from that cohort. Then we have in the phase II expansion, we have two different cohorts. Cohort A is patients who've not received prior treatment, and we see a response rate as reported at ESMO that's in the low 50% range. I believe it was 54%. We've also enrolled a cohort of patients, cohort B, which is a group of patients who've seen prior CSF1R-directed therapy. That could have included Turalio, pexidartinib, or it could have included the investigational antibodies. We saw a response rate that was in the high 40% range. One of the things that was really interesting about that group of patients was that we saw responses in some patients who failed to respond to Turalio or in patients who failed to tolerate prior treatment. We think that's quite encouraging because remember, in this disease. Fortunately, patients don't succumb to TGCT, so they live an otherwise normal life. Having an opportunity, as we did in the phase I, II, to demonstrate activity in patients who've seen prior treatment, we think could be instructive in terms of what the longer-term potential of the brand could be. You know, also notable from the ESMO data update was the drug was well-tolerated. We certainly saw on-target adverse events or side effects. We haven't seen what has been troublesome for Turalio, which is cholestatic hepatotoxicity, and that's the reason that Turalio has a black box warning in the U.S. and is the subject of a REMS program because patients can experience potentially fatal hepatotoxicity. That is an off-target effect, which we have not seen with vimseltinib. We continue to be very encouraged by the profile, and we believe that the profile of the drug suggests that it has the potential to be best-in-class for the treatment of this disease. We're excited about how the data are emerging. The MOTION Study, now is enrolling, the Phase III MOTION Study, and we just announced, last week that we expect to complete enrollment in MOTION in quarter 1. Our prior guidance had been in the first half, so we've been really pleased with how rapidly that study has enrolled and that will then enable us to read out the MOTION Study in quarter 4 of this year. Just remind us of the design of the MOTION Study and, you know, what are some of the assumptions in terms of how the drug and the control arm might perform? Good question. The study is modeled after the pivotal study that was used for the pexidartinib approval, and this was based on regulatory input. It's a 120-patient study. Primary endpoint is response at a time point, which is at six months. And the study's being run in the U.S. and outside of the U.S. We're looking at a dose of 30 milligrams twice weekly for vimseltinib versus placebo, so it's a placebo-controlled study. We, of course, based on the ENLIVEN data, wouldn't expect to see responses in the placebo arm. And we now know from our ESMO data update that we have a very active drug in this disease. We think we have a high probability of a successful outcome in this phase III study, in the MOTION Study. One of the reasons that this program is so exciting to us, not only because of the best-in-class profile that we see with this drug, but also because of the overlap with our existing business. The prescriber base is virtually the same in the U.S. for TGCT as it is with GIST, so 90% overlap in prescribers. We see the opportunity for substantial commercial synergy. Great. I think a lot of investors are trying to get their arms around the commercial opportunity in TGCT. I know you've done a lot of work there, but, you know, how should we think about the initially addressable patient population and the sort of peak sales potential in that? Yeah. We see the total addressable market opportunity in the U.S. as being $850 million, which we think is candidly, a fairly conservative view of that addressable market opportunity. What underpins that number is a very thorough analysis of medical and pharmacy claims that we conducted in the U.S. When we look at the claims analysis, we can see in the U.S. today that there are 1,300-1,400 new patients each year that are treated systemically for their TGCT. We also know that 70% of those patients are getting imatinib treatment today. From the claims data, we know that imatinib is used for about 18 months. In order to come up with our total addressable market estimate, we took both the number of patients that we see treated today, along with the 700-1,000 patients each year who recur after their first surgery. We view those patients as potentially being eligible for systemic treatment. We used the pexidartinib price, we used that 18-month duration of treatment for imatinib that we see in the claims data, and that generates a market opportunity of $850 million. That excludes, by the way, the prevalent pool of patients and it also excludes any calculations for opportunity outside of the U.S. We think the potential is actually quite sizable for a drug like vimseltinib in TGCT, and that's one of the reasons we think together with QINLOCK, there's a peak revenue opportunity here for the products themselves that is likely in excess of $1 billion. Great. In the last couple minutes, maybe then switching over to DCC-3116, which is your ULK1/2 inhibitor. Again, we've seen a little bit of data last year. Can you just remind us of sort of the overall opportunity for the drug and again, what will we learn this year in terms of your ongoing studies? Yeah. We're really excited about 3116. You know, we're the first into the clinic with an inhibitor targeting ULK. This is the initiating factor in the autophagy pathway, which has been widely reported as an escape pathway in cancer when cancers are treated with targeted agents. We've generated a raft of preclinical data now and published that showing that this is in effect with KRAS G12C inhibitors, with MEK inhibitors, with a variety of agents. The first data report that we had from the phase I monotherapy part of the study last year, we were very pleased to see dose-dependent PK. When we reported the data, we saw a really good PD effect to know that now in humans that we're able to see the ability of 3116 to address autophagy in patients. The drug was well-tolerated as monotherapy, which is very important because our approach here, as you know, is a combination approach. We've now started combination cohorts with binimetinib and trametinib, the two MEK inhibitors, as well as sotorasib, the KRAS G12C inhibitor. We plan to present data, updated data from the phase I monotherapy dose escalation part of the study, but also importantly for the first time, the combination dose escalation data later this year. We're really pleased to be advancing the program as quickly as we are and are looking forward to generating additional data. What are some of the, you know, high probability of success opportunities for the drug? There are a variety of different opportunities with 3116 in combination with a variety of different agents. What we're really trying to do in these combination cohorts is test a variety of hypotheses. The first is together with the MEK inhibitor, we've generated a tremendous amount of preclinical data showing the effect and combination both with benni as well as with trametinib. We've generated data with sotorasib and adagrasib. We started our cohort with sotorasib because it was commercially available at the time as the first approved agent. We're testing that hypothesis and we're excited to report those data later this year. We'll present also in the first half of this year additional preclinical data with additional combinations. Once we generate these initial combination dose escalation data, we'll then be in a better position to talk about where we're gonna take the drug from there based on what we see. Great. Well, with that, I think we can wrap up. Looking forward to the vimseltinib phase III data by the end of this year and then more from 3116 as well. Yeah. Thanks, Michael. Great. Thanks, Steve. Really appreciate it. Appreciate it.